DA 1 Flashcards
Dopamine in the mammalian brain
Dopamine neurons less than 0.0002% of total neurons in the brain, HOWEVER, dopamine is a diffuse modulatory transmitter
What are the features of diffuse modulatory transmission?
Projections from remote and sparse nuclei; massive axonal divergence
How many striatal synapses does each dopaminergic neuronal of the substantia nigra have?
Approximately 500,000
Which disorders and processes is dopamine in?
Schizophrenia, Parkinson’s disease, reward, addiction
Which inhibitory transmitter is important with respect to dopamine?
Glutamate
Holtz 1939
Identifying the source of adrenaline found L-DOPA guinea pig extract -> contains a product raising blood pressure
Holtz 1947
Self injected L-DOPA, and found dopamine in urine
Goodall 1951
dopamine in mammalian tissues
Carlsson 1959
Chemical assay for dopamine, 80% in the basal ganglia
Dopamine synthesis pathway
Diagram
Is tyrosine dietary or essential?
Tyrosine is dietary
Levodopa and the blood-brain barrier
Transported across the blood-brain barrier, not found in nature (catecholamines (dopamine like) are!)
Tyrosine hydroxylase
Humans 4 Splice variants TH-1,2,3 & 4, Req. Tetrahydrobiopterin (BH4) &
Fe2+ cofactors + O2
Rate limiting enzyme – [tyrosine] is high but [L-DOPA] is v. much lower
TH activity regulated by [DA] – end point inhibition
Tyrosine hydroxylase kinetics
slightly different kinetics but all involved in the same reaction
Oxygen and tyrosine hydroxylase
Oxygen produces free radicals, and it is higher in dopaminergic neurons, thus these neurons are more likely to kill themselves
Oxygen, enzymes and neurones
Oxygen is a common cofactor in enzymatics but not neurotransmitters probably because of the free radical issue
DOPA decarboxylase
DDC is actually L-Aromatic Amino acid Decarboxylase (AADC)
Cytoplasmic enzyme, 2 splice variants
Cofactor: pyridoxal phosphate (from Vitamin B6) AADC is inhibited by Benserazide, Carbidopa
AADC pathway
Diagram
Release and reuptake of dopamine
Diagram
VMAT1
Neuroendocrine tissues not
brain, for example chromaffin cells
VMAT2
Brain, inhibited by Reserpine
DAT
Dopaminergic neurons (surface of axon terminals and dendrites, not somata)
dopamine catabolism
Diagram
Catechol O-Methyl Transferase
Substrates: DA and NA
Widely distributed: liver, kidney highest
